Recently, cancer patients undergoing chemical therapy, patients who receive organ implants, and patients with HIV or AIDS have been reported to be at an increasingly great risk of fungal infection, mostly from opportunistic pathogens, such as Candida spp., Aspergillus spp. and Cryptococcus neoformans. Currently commercially available antifungal agents against these pathogens suffer from disadvantages of toxicity to the body and therapeutic activity against a narrow range of fungi. As patients having low immunity are currently increasing in number and contracting serious fungal infections, there is an increasing demand for antifungal agents that have excellent inherent pharmacokinetic characteristics and potent inhibitory activities against a broad spectrum of fungi.
A number of derivatives having antifungal activity are known, and have been developed for the treatment of mammals, including humans, infected with fungi. For example, orally available triazole derivatives were reported in the late 1980s, and are represented by Fluconazole (GB Pat. No. 2099818), Itraconazole (U.S. Pat. No. 4,267,179) and particularly, Voriconazole (EU Pat. No. 0440372). None of them, however, are sufficiently satisfactory for use as medicine in that they do not exhibit all of excellent inhibitory activity against some of the opportunistic fungi which cause fatal infections in patients having decreased immunity, good safety, and suitable pharmacokinetics within the body. There is therefore a need for a compound that is highly safe and easily absorbed by the body and has highly potent fungicidal activity.
Many of the antifungal agents which have been developed or are now under study have been found to have additional heterocyclic substituents plus triazole. For instance, fluconazole has a five-membered heterocyclic compound, while a six-membered heterocyclic ring is contained in voriconazole. In addition, isoxazole (EU Pat. No. 0241232, Shionogi Co.) and triazolone (EU Pat. No. 0659751, Takeda Co.) have respective five-membered heterocyclic compounds. Pyrazole rings are found in the compounds disclosed in JP 3415865 by Takeda Co., in WO 2001/79196 by Basilea Co. and in EP 0308782 by Bayer Co. The compounds of the above-mentioned patents are, however, different in structure and antifungal activity from the substituted phenyl-pyrazole derivatives of the present invention. Substituted pyrazole derivatives are also known to have antifungal activity (U.S. Pat. No. 5,705,453, EU Pat. Nos. 1171437, 0308782 and 0234499). Nowhere are triazole derivatives having substituted phenyl-pyrazole structures according to the present invention disclosed in these patents. The conventional compounds are quite different in chemical structure from the compounds of the present invention.